Presently, the Huisgen cycloaddition reaction is one of the most widely-known 3+2 cycloaddition reactions. First mentions of this reaction come from the works of Michael at the end of the 19th century[1] and the most important advances in the uncatalyzed variant of this reaction were brought by the work of R. Huisgen in the second half of the 20th century [2,3]. The beginning of the 21st century brought rapid development in the field thanks to the catalytic variants of the reaction using copper(I) (CuAAC) [4-7] and ruthenium(II) (RuAAC) [8,9]. Compared to the uncatalyzed variant, they allow to regioselectively obtain 1,4- and 1,5-disubstituted 1,2,3-triazoles (Scheme 1).

Thanks to its regioselectivity and high yields, the catalyzed Huisgen cycloaddition variants found a broad range of uses in multiple fields of chemistry and related disciplines.
The applications of the cycloaddition reaction include the synthesis of novel biologically active compounds or tagging of biomolecules or even whole cells/cell fragments in living systems. A more detailed description of these uses can be found in a number of review articles concerning biological chemistry, pharmacy and drug design [10-14], as well as materials science and polymer research [15,16].
In 2001, Sharpless[4,6] and Meldal [5,17] independently showed that copper(I) ions catalyze the Huisgen cycloaddition reaction. This discovery together with the “Click chemistry” concept, presented by K. B. Sharpless [4] initiated rapid growth of interest in this reaction in recent years.
This allowed to identify a number of problems and limitations of these reactions as well as to develop a number of advanced variants overcoming these limitations [18]. One of these solutions is use of ligands complexing copper(I) ions to increase the efficacy of the reaction.
The U.S. Pat. No. 7,375,234 patent concerns the copper(I) catalyzed cycloaddition of azides and alkynes (further abbreviated CuAAC). A cycloaddition process was revealed, not including the addition of an amine or a ligand.
The U.S. Pat. No. 7,763,736 B2 patent discloses a reaction proceeding in an aqueous solution of an alcohol and use of amine or ligand such as e. g. TBTA.
A number of ligands used for the CuAAC reaction are also known. These ligands can be divided into two categories, depending on the chemical nature of metal-interacting electron pairs. These are the “hard” and “soft” ligands. [19,20] Cu(I) is considered a “marginally weak” Lewis acid.[21]
The “soft” ligands include phosphines containing a single bond coordinating to the Cu atom. Examples of these are Cu(P(OMe3)3Br,[22] (EtO)3PCuI [22] and Cu(PPh3)3Br.[23,24] The mentioned complexes are most commonly used when the insolubility of Cu(I) species becomes a significant problem. For CuAAC reactions performed in toluene and dichloromethane, bis(phosphine) complexes like Cu(PPh3)2OAc are efficient.[25]
Information concerning the use of Cu(I) complexes with N-heterocyclic carbene (NHC) ligands in CuAAC have been disclosed.[26,27] The copper concentrations used for these reactions can be reduced to ppm level.[28] The most-often used NHC ligands are [(SiMes)CuBr][29] and [(SiPr)CuCl].[30]
The “hard” ligands have been dominated by amines and it is the nitrogen atom-based structure that is dominant within the CuAAC ligands.[31] The most important catalytic ligand for CuAAC is TBTA [32] (Scheme 2, below). Due to the poor aqueous solubility of TBTA, water-soluble ligands such as THPTA have been designed, including polar substituents aimed to increase the ligand's solubility in aqueous media.

Among the “hard” N-donor ligands, tris(triazolyl)methanol derivatives [33,34] should also be mentioned, as well as 4-(2-pyridil)-1,2,3-triazole, proposed by Fukuzawa et all. [35], and the concept of using 2-ethynylpyridine as a reaction-accelerating additive (In situ generated catalytic ligand).
Further cycloaddition ligands and their uses have been disclosed in patent applications published as WO2012021390 and WO2009038685.
Three fundamental types of technical problems with the present 3+2 cycloaddition ligands can be distinguished. The first one is limited efficacy of the known aromatic ligands for aliphatic substrates.
Second problem is the difficulty in removing the catalytic ligand from the reaction product.
The third one is limited number and relative complexity of the known water-soluble CuAAC ligands.
Unexpectedly, the abovementioned problems have found solution in the subject invention.